Pentraxins are a superfamily of proteins characterized by a pentameric structure1. The classical short-pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP) are acute phase proteins in man and mouse, respectively, produced in liver in response to inflammatory mediators2,3. Pentraxins bind various ligands and are involved in the innate resistance to microbes and scavenging of cellular debris and extracellular matrix components1,4-6.
Long-pentraxins are characterized by an unrelated N-terminal domain coupled to a pentraxin-like C-terminal domain7. The prototypic long-pentraxin PTX38,9 is a 45 kD glycosylated protein predominantly assembled in 10-20 mer multimers10. PTX3 is locally produced and released by different cell types, in particular by mononuclear phagocytes, dendritic cells and endothelial cells, in response to primary inflammatory signals11. Studies in ptx3−/− mice have shown that this molecule plays complex non-redundant functions in vivo, ranging from the assembly of a hyaluronic acid-rich extracellular matrix, to female fertility and to innate immunity against diverse microorganisms12,13. This is related, at least in part, to the capacity of PTX3 to bind with high affinity the complement component C1q, the extracellular matrix protein TSG6 and selected microorganisms, activating complement activation and facilitating pathogen recognition by macrophages and dendritic cells1,14. Thus, PTX3 is a soluble pattern recognition receptor with unique non-redundant functions in various pathophysiological conditions1,14.
Fibroblast growth factor-2 (FGF2) is a heparin-binding growth factor that induces cell proliferation, chemotaxis, and protease production in cultured endothelial cells by interacting with high affinity tyrosine-kinase receptors (FGFRs)15. FGF2 induces angiogenesis in vivo and modulates neovascularization during wound healing, inflammation, atherosclerosis, and tumor growth16. Several molecules sequester FGF2 in the extracellular environment, thus preventing its interaction with endothelial cell FGFRs and inhibiting its angiogenic activity (reviewed in16). Many of these inhibitors are produced/released locally and/or systemically, thus underlying the complex tuning of the angiogenesis process.
Long PTX3 binds FGF2 with high affinity and specificity. Accordingly, long PTX3 inhibits FGF2-dependent endothelial cell proliferation in vitro and angiogenesis in vivo17. Also, whole PTX3 inhibits FGF2-dependent smooth muscle cell activation and intimal thickening after arterial injury18. Thus, PTX3 may potentially contribute to the modulation of FGF2 activity in different pathological settings characterized by the co-expression of the two proteins, including inflammation, wound healing, atherosclerosis, and neoplasia. However no therapeutic use of the protein is disclosed given the unfeasibility to utilize such large molecule and to other activities of the protein. As a matter of fact, PTX3 binds C1q via the C-terminal pentraxin domain10.
At present, no biological functions have been ascribed to the PTX3 N-terminus. On this basis, the authors have investigated the ability of PTX3 N-terminus to interact with FGF2.